Spinal Cord Implants for Nerve Regeneration
by
Lara Suzanne Abbaschian
B.S., Materials Science and Engineering (2001)
Massachusetts Institute of Technology
Submitted to the Department of Materials Science and Engineering in Partial Fulfillment
of the Requirements for the Degree of
Master of Engineering
at the
Massachusetts Institute of Technology
MASSACHUSETTS NS Tm/E
OF TECHNOLOGY
September 2004
FEB 1 6 2005
© 2004 Massachusetts Institute of Technology
All rirhts reserved
LIBRARIES
/
Signature
ofAuthor..............................:.................
Department of Materials Science and Engineering
August 6, 2004
Certified by ...................
.....................................................................
Professor Robert S. Langer
Germeshausen Professor of Chemical and Biomedical Engineering
o-C TXTsis
Supervisor
Certified by ......................................
..
Pofessor Michaeil . Cima
Sumitomo Electric Industries Professor of Engineering
Thesis Reader
Accepted
Car
Carl V. Thompson
Thompson II.............
II
Stavros Salapatas Professor of Materials Science and Engineering
Chairman, Departmental Committee on Graduate Studies
ARCHVIES
Spinal Cord Implants for Nerve Regeneration
by
Lara Suzanne Abbaschian
Submitted to the Department of Materials Science and Engineering
On August 6, 2004 in partial fulfillment of the requirements for the Degree
of Master of Engineering in Materials Science and Engineering
ABSTRACT
It has only been in the last couple decades that the potential for regeneration in the spinal
cord became accepted. However, there is still no proven method for enabling this
regeneration. An implant model was developed to help aid in repair, recovery, and
regeneration in the spinal cord following spinal cord injury (SCI). This is a polymerbased model with the ability to host neural stem cells.
This document briefly reviews the SCI model developed. It also discusses the intellectual
property surrounding the implant model, as well as examines the possible pathways
through the Food and Drug Administration (FDA) and to the market.
Thesis Supervisor: Robert S. Langer
Title: Germeshausen Professor of Chemical and Biomedical Engineering
2
ACKNOWLEDGMENTS
First and foremost, I would like to thank my advisor, Professor Langer, for all of the
support he has given me during my time in the Langer Lab. I would also like to thank
Dr. Erin Lavik, Dr. Yang D. Teng, Professor Langer, and Dr. Evan Snyder for conducting
the research that is the foundation of this thesis. Dr. Erin Lavik and Dr. Jason Burdick
were also extremely instrumental in guiding me through the graduate experience.
Ying Chau and Grace Kim were indispensable and deserve special mention. I would also
like to thank all my other friends for keeping me sane and happy. And of course, my
amazingly loving family has given me their unrelenting support that has enabled me to be
where I am today.
3
Contents
Page Number
1.0 Introduction
1.1 Spinal Cord Injury Basics
1.2 Spinal Cord Injury Incidence Statistics
2.0 Technology
2.1 Implant Concept
2.2 Implant Model
2.2.1 Adult Rat Hemisection Model Study
2.3 Future Research
5
5
6
8
8
10
10
11
3.0 Intellectual Property (IP)
12
4.0 Market and Business Evaluations
15
4.1 Market Potential for a Spinal Cord Implant System
4.2 Animal and Clinical Trials for the CDRH, USFDA
5.0 Business Plan for Spinal Cord Implant Model
5.1 Approach One
5.2 Approach Two
15
19
22
23
26
6.0 Conclusions
28
References
29
Appendix A: MIT Patents Licensed to GMP Companies, Inc.
31
4
1.0 INTRODUCTION
The novel and early-stage technology being explored in this document is an
implant for the cure of spinal cord injury (SCI). Not so many years ago, it was believed
that there was no hope of regeneration in the spinal cord, but recent research has
suggested otherwise [1]. This has created a unique situation in which there is a fully
developed market with no product. There are many ways to alleviate some of the
problems associated with SCI and cope with the many side effects, but to date there is no
therapy available to promote repair. Full recovery occurs in fewer than 1% of the cases
of SCI, and 45% of people injured do not recover feeling or function below the site of the
injury [2].
1.1 Spinal Cord Injury Basics
Spinal cord injury (SCI) is defined as damage of the nerves either through trauma
or disease. This damage does not necessarily imply a transection of the cord, but is
actually achieved more frequently by contusions of the chord. After the initial trauma,
the injury site actually expands over the course of weeks to months. The mechanisms
following the initial trauma (secondary injury) are not well understood. Between the
initial injury and the secondary degeneration, effects include loss of axonal connection,
lost neurons and glia, epidural and glial scarring, and demyelination of axons. The
perceivable effects of the injury can include impairments or loss of movement/muscle
control, sensations, and organ system control. The seriousness of SCI tends to increase
5
with increasing injury sites: injuries suffered to the neck tend to have more serious
consequences than injuries lower in the spine.
Currently, there are no complete or even semi-partial treatments for SCI. Any
treatment will have to achieve a number of goals. It must (1) eliminate secondary injury,
(2) mitigate the immune response, (3) promote neuronal survival, (4) foster axonal
sprouting, and (5) provide guidance for axonal growth and synapse formation. Present
day approaches and research avenues for treatment of SCI involve:
-Methylprednisolone
-Improves recovery 20% if within 8 hours
*Growth Factors
-Molecules that regulate protein synthesis for cell division and
growth
-NGF (sensory), NT-3 (motor), BDNF, GDNF
-Axonal Guidance
-Carbon fibers, collagen, matrigel
*Myelinreplacement via stem, Schwann, OEC's
*Fetal Tissue
*Stem Cells
Some of these areas have had limited success already, while others are believed to
ultimately not be able to provide a complete cure as they do not address all of the goals
mentioned above [3].
1.2 Spinal Cord Injury Incidence Statistics
The following tables and charts have been compiled by the National Spinal Cord
Injury Statistical Center (NSCISC) and were published December 2003. They contain
data from the 1970's to that date.
6
Entlon- of (£'I il(e 1o0
Sports7 .5%
.Fnll3
u_, 9).
tther 7 Ai
Eon
r I
-1
II
V
UJXI.U
Vehicular Crashes
21.6%
40.9%
Figure 1. Origins of SCI 141
Since 1973 the trends of SCI origin have indicated a decrease in proportion of injuries
from motor vehicle crashes and sports and an increase in the proportion of injuries from
falls and violence. Fifty-three percent of SCIs occur among young adults in the 16 to 30
year old range. Also, 81.2% of all injuries in the database have been for males. The
following tables show life expectancy for individuals based on age at injury and initial
survival rates.
Table 1. Life Expectancy for Persons who Survive the first 24 hours Post-Injury [41
Age at
No
Motor Functional at
Injury
SCI
any Level
Para
Low Tetra
High Tetra
(C5-C8)
(C1-C4)
Ventilator
Dependent
at any Level
20 yrs
57.8
52.9
45.3
40.5
36.0
16.3
40 yrs
38.9
34.4
27.7
23.7
20.1
7.0
60 yrs
21.6
17.8
12.7
10.0
7.7
1.3
7
Table 2. Life Expectancy for Persons who Survive at least 1 year Post-Injury 141
Age at
Injury
No
SCI
Motor Functional at
any Level
Para
Low Tetra
(C5-C8)
High Tetra
(C-C4)
Ventilator
Dependent
at any Level
20 yrs
57.8
53.4
46.0 41.8
38.2
23.3
40 yrs
38.9
34.9
28.3 24.7
21.8
11.1
60 yrs
21.6
18.2
13.2
8.8
2.9
10.7
Until recently, the leading cause of death for those suffering from SCI was renal failure.
However, recent new technologies and care have improved urologic management and
have shifted the balance. The next most frequent causes of death as reported by the
NSCISC are pneumonia, pulmonary emboli, and septicemia.
2.0 TECHNOLOGY
2.1 Implant Concept
A polymer-based implant model has been developed for aiming to cure SCI by
Dr. Erin Lavik at the Massachusetts Institute of Technology in the research group of
Professor Robert Langer in collaboration with Dr. Evan Snyder and Dr. Ted Terry. It has
been designed to be a very flexible model so that as more is learned about the nature of
SCI and the necessary conditions for nerve protection, regeneration, and repair, the model
can be altered to incorporate the necessary features. The overall design of the implant
8
has been created to mimic the architecture of the natural spinal cord. As new tissue is
created in vivo, the polymer will degrade. The figure below is a gives a rough idea of the
implant structure. The length and diameter of the implant can be tailored for each
individual injury. The gray section represents an inner porous sponge to mimic the gray
matter, and the outer half-cylinders provide replacement for the white matter.
Figure 2 Implant Model
Some of the elements to control in this model are the surface chemistry, the role
of pore size in the outer and inner scaffolds, the degradation rate of the scaffold, the
inclusion of drugs and growth factors, the incorporation of microspheres for complex
release profiles, and the incorporation of different cell types prior to implantation. It is
hoped that by incorporating tissue engineering, drug delivery and polymer systems
engineering, the model will be able to embody and keep pace with optimal SCI cures as
they are discovered.
9
2.2 Implant Model
The scaffold selected for the preliminary study was made from a blend of 50:50
poly(lactic-co-glycolic acid) (PLGA) (75%, number average molecular weight, Mn 40,000) and a block copolymer of poly(lactic-co-glycolic acid)-polylysine (25%, PLGA
block Mn _ 30,000, polylysine block M. _ 2000). The degradation rate of the PLGA was
about 30-60 days. The inner scaffold was created via salt leaching and had pores with a
diameter range of 250-500 pmn.The outer scaffold used a solid-liquid phase separation
technique and dioxane sublimation to achieve axial porosity of around 10 m [5,6].
The cells used were murine NSCs (clone C17.2) furnished by Dr. Evan Snyder of
the Departments of Neurology, Pediatrics, and Neurosurgery of Harvard Medical School.
The polymer was functionalized for future possible surface modifications although none
were introduced in the following study. The functionalization was achieved by coupling
PLGA with a carboxyl end group to poly(c-carbobenzoxy-L-lysine) using dicyclohexyl
carbodiimide (DCC) [7, 8].
2.2.1 Adult Rat Hemisection Model Study
An animal study of fifty adult female Sprague-Dawley rats was conducted using a
series of different implant models. There were a total of four different treatments that
could be performed across the group of fifty. All animals had a 4-mm-long hemisection
of their spinal cord tissue removed between the 9h-to-10
h thoracic
spinal vertebrae. The
10
primary control animals (n = 12) received no implant ("lesion control"). A second group
(n = 12) received murine NSCs (clone C17.2) suspended in medium ("cells alone")
delivered to the lesion site. The third group (n = 11) received the polymer implant
without any cells ("scaffold alone"), and the fourth group (n = 13) received the NSCseeded scaffold ("scaffold plus cells"). Standard procedures were followed to minimize
error, bias, and variability in the study.
Various behavioral studies were conducted, biotinylated dextran amine (BDA)
tracing was performed, and general histology and immunocytochemistry on the recovered
tissue was carried out. Extensive details of the animal study as well as the implant model
can be found in Dr. Lavik's thesis [9] and published in the Proceedings of the National
Academy of Sciences [10]. Most notably, one day after the surgery and then weekly,
mobility analysis was conducted by independent observers using the Basso-BeattieBresnahan (BBB) scale. The study concluded after 10 weeks, at which time the spinal
cords were removed, sectioned, and stained for analysis. The results of the study showed
that the "scaffold plus cells" group exhibited the greatest ability for coordinated, weightbearing hind limb stepping. At the conclusion of the study, 69% of the "scaffold plus
cells" group, 54% of the "scaffold alone" group, 17% of the "cells alone" group, and 33%
of the "lesion control" group had achieved a BBB score of 10 or greater. The score of 10
is considered to be the point of "significant walking behavior."
2.3 Future Research
Future research of course involves continued animal studies and eventually
human trials. However, it is equally important to develop an in vitro model to test the
11
many different permutations of the model as well as test future additions and
modifications. Results of the preliminary animal study suggest that the scaffold itself
posed the greatest enabling aspect of the implant. Further studies should be done to
assess the extent to which this is true. As research continues, larger animals will be used
until clinical trials with humans are appropriate.
3.0 INTELLECTUAL PROPERTY (IP)
To assess the breadth available for intellectual property and patent claims, a
search of the United States Patent and Trademark Office (USPTO) was conducted. The
Internet site for the USPTO contains all patents from 1976 to the exact day the search is
conducted. To ensure all potential patents were flagged, all queries were over the entire
body of each patent. This allowed for a breadth that would ideally catch any extra
patents that used similar but not the exact terms of this device.
The first step for a patent search would be to define search terms very narrowly to
match the model as closely as possible. In this case, as was discussed earlier, there are no
comparable patented systems. However, while polymeric implants for treating spinal
cord injury are a novel area of research, the building blocks to get there are not.
Consequently, any implant model must be comprised of non-patented components. It is
also important to make sure that the methods to make the components are free from
patent restrictions as well.
12
A final consideration that may not have crippling implications but is still
important to study is the methods for the research and development of the implant
system. If there are any diagnostic tools or cell stains, kits, or assays, these should be
taken into account with respect to long-term production plans. Once the research moves
from the university to a corporate setting, many of the tools afforded to researchers at low
or no costs may acquire new or higher prices. Therefore, it would be important to try to
avoid a dependence on auxiliary tools for quantitative analysis and product regulation
that have the potential for hefty price tags. Unfortunately, there are certain standard
protocols for cell-systems that may be unavoidable for creating a reputable product.
The first series of searches was conducted to confirm that there were indeed no
spinal cord implant systems patented that could overlap with the discussed model.
Again, the entire patent document was searched; this gives the possibility of a higher
number of non-applicable returns, but reduces the possibility that a relevant patent slip
through the search uncaught. A search on "spinal cord" returned 7,149 results and adding
"scaffold" to the query reduced the number to 132. Further reducing the field to 10,
"PLGA" was included, but none of those patents were at all applicable to this model and
application. Along another track, the search on "nerve regeneration" returned 567
patents, adding "scaffold" narrowed the number to 72, and then "PLGA" cut it to 12.
Again though, none of the returned patents were relevant.
The next series of searches was conducted with "Robert Langer" as an author.
Professor Langer has over 800 articles, 420 abstracts, and over 500 issued or pending
patents. This implant model was actually developed with the intent of piggybacking his
patents so that any positive results could be investigated without worrying about
13
intellectual property infringement. Appendix A lists some of the patents currently
relevant to the implant.
Even though the enormous number of patents under Professor Langer's name
afford a lot of leeway for research avenues, it is still important to be diligent in
considering the many components of the model. Because the model has many layers to
it, the materials analysis of IP should include, but not be limited to, PLGA, PLA, PLGAPLA block copolymer, and functionalized block copolymers. These materials should be
combined with the methods of salt leaching and oriented pore creation via dioxane
sublimation for the investigation of IP as it relates to processing. Finally, the broader
ideas of polymers for tissue engineering, cells plus polymer systems, three-dimensional
scaffolds, various drug delivery methods, and growth factor use should also be
considered.
Currently the implant model has a very wide range of embodiments as many
factors can be modified as well as switched. This versatility is wonderful in the
laboratory setting as it facilitates much experiment mobility. However, getting a solid
patent on such a device becomes challenging. It will be important to isolate certain
features of the device quickly and protect them first, and then gradually expand the IP of
the product as research and clinical studies support the other different facets of the model.
14
4.0 MARKET AND BUSINESS EVALUATIONS
The impact on the quality of life for an individual who suffers from SCI that a
successful spinal cord implant would have is astronomical. And as will be discussed in
the following sections, there are a great number of individuals who suffer from SCI and
at a great personal cost. However, that alone is not enough to bring the system to market
or even make it available to a select few. After the following market analysis, this
section will then summarize the requisite interactions with the U.S. Food and Drug
Administration (FDA), the organization the monitors and regulates all medical devices.
Finally, a rough business plan will be outlined to specify short, medium, and long-term
goals.
4.1 Market Potential for a Spinal Cord Implant System
Since 1973 there has been a national program for an SCI data center. From 19731981, it was the National Spinal Cord Injury Data Research Center, and from 1983 to the
present, it has been the National Spinal Cord Injury Statistical Center (NSCISC). The
following data comes from Spinal Cord Injury Facts and Fiures
at a Glance.
Information Sheet, December 2003 [4]. It is estimated that over 10,000 people in
the United States suffer some degree of SCI each year. The International
Campaign for Cures of Spinal Cord Injury Paralysis provides the following table
summarizing the published data on SCI.
15
Table 3. International Prevalence and Costs [111
Countryl
nJuresl annum
Popultion
and,rato
Estimated
anrual cost
Direct GovL
investment In
SC, cure
(Local
Currentcy)
related
$7.736 billion
(USD)
70 million
$1.5 billion
6 million
(CDN)
HtIng wh SCI
(millions)
USA
10000
(260)
(40)
CANADA
843
·(30)..
(27)
UK
35,000
(59)
700
(12)
AUSTRALIA
241
10000
(17)
(125)
(13.2)
2665
(21.3)
TURKEY
1000
(61)
(16.9)
TAIWAN
1353
(16.6)
GERMANY
1500
(81)
(18.5)
JAPAN
250,000
30,000
(Cp"
>500 Mill
(GBP)
$1.0 Biilion
(IUS}
resarch
(USD)
NYK*
2 million
(AUS)
II
NETHERLANDS 439
(16)
ITALY
700
(58)
(12)
JORDAN
(4)
70
FIJI
(18)
16
(.75)..
(18;.7)
I
11,864
I
=l
RHONE ALPS
II=
FRANCE
regional
DENMARK
regional
(12.7)
-(9.2)
CHINA
(1200)
PORTUGAL
10,000
(8.4)
CENTRAL
REGION
sub total
(1582)
(57.8)
29,527
(14.23)
420,000
-760,000 (6
nations)
16
62868
REST OF
WORLD
(44-18)
_
·_·
(14.23)
·
__
·
92,395 NEW
CASES / YR
TOTAL
· ·_
·
2 million
conservatively
$10 billion in
4 of 200
-
perhaps $150
million
nations
Furthermore, the organization estimates that by the close of 2005, 2.5 million
people will be living with SCI-induced paralysis. With an estimated cost of $10 billion in
four nations alone and somewhere on the order of $150 million spent on research for
finding a cure to SCI, there is great market potential for the right device. In the U.S, the
NSCISC estimates that an injury sustained at age 25 that results in any minimal loss of
motor function at any level will cost that individual over $500,000 in his lifetime. The
following two tables delineate the average yearly expenses and the lifetime costs,
respectively, for individuals with varying levels of SCI.
Table 4. Annual Costs for an Individual [41
Average Yearly Expenses
(in 2000 dollars)
Severity of Injury
First Year Each Subsequent Year:
High Tetraplegia (C1-C4)
$626,588
$112,237
Low Tetraplegia (C5-C8)
$404,653
$45,975
Paraplegia
$228,955
$23,297
Incomplete Motor Functional at any Level $184,662 $12,941
· ..
/
.
17
Table 5. Lifetime Costs for an Individual [41
Estimated lifetime costs by Age at Injury
(discounted at 2%)
Severity of Injury
25 years old 50 years old
High Tetraplegia (Cl-C4)
$2,393,507
$1,409,070
Low Tetraplegia (C5-C8)
$1,353,360
$857,050
Paraplegia
$799,721
$545,460
Incomplete Motor Functional at any Level $533,474
$386,619
This data further supports the idea that there is a great deal of money circulating
due to SCI. The motivations for an implant to come to the market may not exist for the
healthcare industry or for individual doctors, but certainly, the market does exist in terms
of the desire of injured individuals and their families. Later in this section the path to
market will be discussed in greater depth.
Besides the Langer Lab at MIT, there are many other centers for research on
nerve regeneration in the spinal cord. Because the research is so expensive and
fundamental, currently there is very little industry involvement in the field. Some of the
extensive United States research programs in academia have been established at MIT,
Harvard, University of Miami, University of Louisville, the University of Alabama at
Birmingham. Research is not only being conducted domestically, but there are also
programs in Europe and Australia working to find a cure for SCI. Additionally, the U.S.
government funds a 16 Model SCI Systems which exist to "demonstrate improved care,
maintain a national database, participate in independent and collaborative research and
provide continuing education relating to spinal cord injury." These centers are spread
throughout the U.S. and can be regarded as the premier sites of cutting-edge SCI
18
research. The funding they receive for their roles as Model Systems comes from the
National Institute on Disability and Rehabilitation Research (NIDRR), Office of Special
Education and Rehabilitative Services, US Department of Education. All of the above
groups should be regarded as competitors for the SCI market even though there is a great
deal of collaboration that takes place. However, there is an enormous range of tactics for
curing SCI being investigated, and thus the groups are not competing for the same
technology, rather the same ends. As such, it will most likely be that the product or
approach that best achieves these ends will have control of the market.
4.2 Animal and Clinical Trials for the Center for Devices and Radiological Health,
United States Food and Drug Administration
Any medical devices that are going to be tested in animals or humans are subject
to regulations by the Center for Devices and Radiological Health (CDRH), a division of
the U.S. Food and Drug Administration. Even though this poses major cost and research
burdens and can be regarded as an unnecessarily lengthy process, the act of getting FDA
approval can also serve to convince peer researchers of the merits of the implant model.
All medical devices are categorized as Class I, Class II, or Class III, with Class III being
the most highly regulated and monitored division. This implant model falls into the Class
III range of devices, defined as "those that support or sustain human life, are of
substantial importance in preventing impairment of human health, or which present a
potential, unreasonable risk of illness or injury." In fact, the FDA regards all spinal
systems as "significant risk devices." As such, an Investigational Device Exemption
19
(IDE) is necessary before any sort of clinical data can be obtained. The IDE must
include (1) the nature and design of the device, (2) risk analysis, (3) patient safety, (4)
manufacturing and monitoring, (5) clinical protocol and consent forms, and (6) the
institutions and investigators, etc. for the study.
Obtaining an IDE and completing some of the clinical trials then prepare the way
for obtaining the Premarket Notification 510(k) or Premarket Approval (PMA). In the
case of this Class III medical device, a PMA is required. The CDRH's overview of the
PMA is given below. This introduction highlights the extensive knowledge and proof of
such knowledge that one must supply for any approved device.
PMA is the most stringent type of device marketing application required
by FDA. The applicant must receive FDA approval of its PMA
application prior to marketing the device. PMA approval is based on a
determination by FDA that the PMA contains sufficient valid scientific
evidence to assure that the device is safe and effective for its intended
use(s). An approved PMA is, in effect, a private license granting the
applicant (or owner) permission to market the device. The PMA owner,
however, can authorize use of its data by another.
The PMA applicant is usually the person who owns the rights, or
otherwise has authorized access, to the data and other information to be
submitted in support of FDA approval. This person may be an
individual, partnership, corporation, association, scientific or academic
establishment, government agency or organizational unit, or other legal
entity. The applicant is often the inventor/developer and ultimately the
manufacturer.
FDA regulations provide 180 days to review the PMA and make a
determination. In reality, the review time is normally longer. Before
approving or denying a PMA, the appropriate FDA advisory committee
may review the PMA at a public meeting and provide FDA with the
committee's recommendation on whether FDA should approve the
submission. After FDA notifies the applicant that the PMA has been
approved or denied, a notice is published on the Internet (1) announcing
the data on which the decision is based, and (2) providing interested
20
persons an opportunity to petition FDA within 30 days for
reconsideration of the decision.
The regulation governing premarket approval is located in Title 21 Code
of Federal Regulations (CFR) Pal-t814, Premarket Approval. A class III
device that fails to meet PMA requirements is considered to be
adulterated under section 501(f) of the FD&C Act and cannot be
marketed. [12]
Below is the listing of scientific elements that the researchers (assumed to be the
PMA applicants in this case) must provide. As with IP and patent claims as well, the
language of the regulations is very often used to make claims or defend decisions. As
such, the requirements were not summarized but rather are given as reported by the
CDRH.
Data Requirements
A Premarket Approval (PMA) application is a scientific, regulatory
documentation to FDA to demonstrate the safety and effectiveness of the
class III device. There are administrative elements of a PMA
application, but good science and scientific writing is a key to the
approval of PMA application. If a PMA application lacks elements listed
in the administrative checklist, FDA will refuse to file a PMA
application and will not proceed with the in-depth review of scientific
and clinical data. If a PMA application lacks valid clinical information
and scientific analysis on sound scientific reasoning, it will delay FDA's
review and approval. PMA applications that are incomplete, inaccurate,
inconsistent, omit critical information, and poorly organized have
resulted in delays in approval or denial of PMA applications.
Manufacturers should perform a quality control audit of a PMA
application before sending it to FDA to assure that it is scientifically
sound and presented in a well organized format.
Technical Sections: The technical sections containing data and
information should allow FDA to determine whether to approve or
21
disapprove the application. These sections are usually divided into nonclinical laboratory studies and clinical investigations.
Non-clinical Laboratory Studies' Section: Non-clinical laboratory
studies' section includes information on microbiology, toxicology,
immunology, biocompatibility, stress, wear, shelf life, and other
laboratory or animal tests. Non-clinical studies for safety evaluation
must be conducted in compliance with 21 ( 1R ,r!:t5S (Good Laboratory
Practice for Nonclinical Laboratory Studies).
Clinical Investigations' Section: Clinical investigations' section includes
study protocols, safety and effectiveness data, adverse reactions and
complications, device failures and replacements, patient information,
patient complaints, tabulations of data from all individual subjects,
results of statistical analyses, and any other information from the clinical
investigations. Any investigation conducted under an Investigational
Device Exemption (IDE) must be identified as such.
Like other scientific reports, FDA has observed problems with study
designs, study conduct, data analyses, presentations, and conclusions.
Investigators should always consult all applicable FDA guidance
documents, industry standards, and recommended practices. Numerous
device-specific FDA guidance documents that describe data
requirements are available. The guidance document database on the
Internet
can
be
found
at
!h
l
:_.t':\5
cSatal.
C
sci
ipts.c
cdrhic
tdocs,'c(i( i
'Scarcih.cifmi.
Study protocols should include all applicable elements described in the
device-specific guidance documents. [12]
5.0 BUSINESS PLAN FOR SPINAL CORD IMPLANT MODEL
As has been detailed above, the market for a cure for SCI is enormous not only in
the U.S. but in the world. It is also a longstanding market that will not disappear with
time. There is also an enormous advantage to being the first company to begin to capture
the market, as there are over 250,000 people alive today in the U.S. suffering from SCI.
22
The U.S. injury rate of 11,000/year could be taken as some measure of the future national
market size.
In this section, two pathways to market will be discussed. The first one approach
represents a more typical plan of attack than the second approach, which details the
actual chosen direction for the future of the SCI implant research.
5.1 Approach One
A feasible product timeline is given below. Because of the nature of tissue
engineering research, exact dates were not hypothesized as each step has such a variable
duration.
Table 6. Anticipated Steps to Market
Step 1
Step 2
Step 3
Step 4
Step 5
-Refine Model
-Repeat Studies
-Streamline
Production
-Move from
MIT setting
-IDE
-Primary
patents
-FDA clinical
trials
-Product used
at select
hospitals
-Doctor
Education
-Market
Dominance
The first steps involve more fundamental research into the implant and system. It
would be greatly advantageous to have a thorough in vitro model developed to test the
different implant parameters to supplement and direct the animal studies. Also, it would
be helpful at this time to start developing a method to regulate implant production to
ensure consistency. This is somewhat implicit in conducting proper animal trials, but it is
23
important to stress this step as automating the production of implants will be out of the
question until much later in the development process.
During this research period, all work can be kept at MIT. This keeps the door
open for a breadth of funding and collaboration not available in the corporate setting. In
the financial year of 2000 alone, the International Campaign for Cures of Spinal Cord
Injury Paralysis (ICCP) funded over $25 million in research projects. However, it also
keeps all IP as joint property of MIT, so this must be factored in when computing the cost
balances. Collaborations can also be established at this time with potential surgeons to
perform the first series of surgeries. As this is a high-risk for low-yield research area, it
is important to identify surgeons who have a scientific curiosity and desire for medical
progress who won't be swayed by skepticism from peers or financial motives.
In the second stage, the move from MIT and the beginning of FDA interaction, an
off-campus laboratory site will need to be acquired. At this point, it will be necessary to
look elsewhere for supplemental funding. Some research money will still be available,
but it is important to expect much of it to be linked to university settings. Venture capital
firms are one consideration. In the past 10 years, $40+ billion has been invested in the
U.S. by such firms in the medical device/biotech field [11]. However, the "easy" money
may not be enough to offset the consequences- loss of decision-making control, loss of
complete ownership, etc.- that are well-known requirements for interaction. Another
funding supplement could come from "angel" investors; the area of SCI actually is a
very likely place for these people or organizations to exist. Finally, supplements for
small businesses should be explored and the resources of the United States Small
Business Administration organization tapped.
24
The FDA clinical trials for obtaining the PMA (roughly the third stage) will also
be quite expensive. At this point, in conducting a cost analysis for business strategy one
should make the decision between keeping all research "in house" or employing a
Contract Research Organization (CRO) to help with the many aspects of research needed
to create a comprehensive case to submit to the CDRH. CRO's can offer services for
clinical trials such as:
Bibliography analysis
Clinical investigation plan and final report preparation
Investigator brochure and interface with physicians and hospitals
Design of Case Report Form (CRF)
Interaction with ethical committee
Selection of investigators, investigation sites, study monitoring and inspection
Data management, result evaluation and statistical analysis
Clinical risk analysis
Assistance in regulatory submissions
Materiovigilance [13].
However, the infrastructure may already be present in the company for conducting these
processes as a result of the previously completed research and such outsourcing may not
be cost-effective.
Finally, the implant will be ready and approved for human surgeries. At this
stage, the surgeons brought on board during the first steps of the project will become
indispensable. They will be responsible for successful surgeries and, just as importantly,
for educating the medical community. Initially, surgery for the implantation of the model
will only be available through these surgeons. Giving these doctors this luxury of initial
exclusivity will provide the necessary incentive for their participation in the research and
company. The recognition for scientific advancement will hopefully prove successful in
motivating the surgeons to help bring the model to the forefront of the medical
community, as there is monetary incentive for the larger hospital organizations to keep
25
the current SCI treatments in place. Finally, the structure of the national SCI Model
Systems could be exploited to provide enough centers throughout the U.S. for patients to
receive the surgery.
5.2 Approach Two
As can be seen from the above approach, the process of getting an implant to
market has many levels and variables and requires a good amount of expertise in a
variety of areas. The actual approach selected to continue pursuing this technology was
to enter into collaboration with GMP Companies, Inc. [14] The company uses an intense
technology evaluation process to select various pharmaceutical, diagnostic, and medical
device technologies to "drive innovations through every step of research, development,
and commercialization." GMP requires that the technology meet the following criteria:
·
·
·
·
·
·
High impact on society by serving an unmet need
Obviousness - an idea that is easy to explain and to understand
Accomplished innovators with proven track records
Ahead of its time - ground breaking clinically and scientifically
Strong intellectual property protection - patentability and freedom to operate
Long product life cycles in large markets
Significant potential profit margins [15]
It is evident from this list that the SCI technology being discussed is a natural fit for the
ideal GMP technology.
Once the technology has been selected by GMP, the appropriate patents are
licensed from the host so that GMP can work freely with the product. The incentive for
collaboration with GMP is that they will help provide a streamlined, efficient process for
26
getting the technology into production. They do so by "strategic relationships" with
companies such as 3M, Motorola, P&G, Medtronic, Hillenbrand Industries, and Quest
Diagnostics. They also have a network of scientific advisors who are considered to be
the top researchers in their respective fields. Included in this group are Professor Langer,
Dr. M. Judah Folkman, Dr. Brem, and Dr. Joseph P. Vacanti, who would all be able to
give important insight for the SCI technology development. Specifically, in exchange for
licensing the technology to GMP, they offer to:
·
·
·
·
·
Provide the R&D, medical, business, financial and legal resources necessary to
move promising product candidates forward
Develop protocols for pre-clinical research and clinical trials that facilitate
movement through the regulatory process
Develop a broad spectrum of programs including business development, product
design, marketing and sales
Provide a comprehensive team of legal and regulatory specialists with expertise in
the areas of patent and intellectual property and FDA regulations
Listen closely, respect confidentiality and work collaboratively to develop and
commercialize promising technologies in a timely manner [15]
Fourteen MIT patents have been licensed to MIT, on thirteen of which Professor
Langer is listed as an Inventor. Listed in Appendix A, these patents protect the wide
range of research avenues for the SCI implant. It is also important to note that seven of
these patents have corresponding European and Japanese patents so that the technology is
protected internationally as well. GMP has a special division for Tissue Engineering /
Neurocare headed by Professor Langer, Dr. Vacanti, and Dr. Snyder. They have just
entered into a three-year Sponsored Research Agreement with The Burnham Institute in
La Jolla, California to further research in this division. While research will still continue
at the original institutions as well, the partnership with GMP provides the overall
27
pathway and complete set of resources to bring some form of the implant model to
market.
6.0 CONCLUSIONS
The potential for exploiting the huge untapped market of SCI exists but there are a
few barriers. The first is obviously the development of the proper technology. The
proposed model provides enough flexibility to keep pace with the evolving scientific
understanding of the mechanisms behind SCI and its cure. Next, the FDA regulations
and requirements must be met. Finally, the business model must include a way to
increase acceptance of the implant and find a way to avoid getting blocked by those who
benefit the most from the huge current market of SCI treatment and care. If the clinical
results hold and the FDA can be convinced, a great deal of profit is available especially if
the product is the first to the market. Additionally, the path through the FDA and to the
market is not cleared once one group passes through. Thus there is a certain amount of
buffer available between future product development and their presence (and thus
competition) in the market. Finally, it must be stressed that while this is a technology
that must be treated as all others, if it indeed can become a reality, the global nonfinancial impact will be orders of magnitude greater than monetary profits.
28
REFERENCES
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2. Center, N.S.C.I.S. (University of Alabama, Birmingham, Alabama, 2000).
3. Schmidt, C.E. & Leach, J.B. Neural Tissue Engineering: Strategies for Repair and
Regeneration. Annual Review Biomedical Engineering 2003; 5:293-347.
4. Center, N.S.C.I.S. Facts and Figures at a Glance. (University of Alabama,
Birmingham, Alabama, December 2003).
5. Bellamkonda, R., Ranieri, J.P., Bouche, N. & Aebischer, P. Hydrogel-Based
Three Dimensional Matrix for Neural Cells. Journal of Biomedical Materials
Research 29, 663-671 (1995).
6. Chang, A.S. & Yannas, I.V. in Neuroscience Year, Supplement to the
Encyclopedia of Neuroscience (eds. Smith, B. & Adelman, G.) 125-126 (1992).
7. Hermanson, G.T. Bioconjugate Techniques (Academic Press, San Diego, 1996).
8. Rich, D.H. & Singh, J. in The Peptides: Analysis, Synthesis, Biology (eds. Gross,
E. & Meienhofer, J.) 241-261 (Academic Press, New York, 1979).
9. Lavik, Erin. FunctionalRecoveryfollowingTraumaticSpinal CordInjury
Mediated by a Novel Polymer Scaffold Seeded with Neural Stem Cells, Sc.D.
Thesis, Department of Materials Science and Engineering, MIT (2001).
10. Teng, Y.D., Lavik, E.B., Qu, X.L., Park, K.I., Ourednik, J., Zurakowski, D.,
Langer, R., Snyder, E.Y. (2002) Functional Recoveryfollowing traumatic spinal
cord injurymediatedby a uniquepolymer scaffoldseededwith neuralstem cells.
Proc Natl Acad Sci USA 99:3024-3029.
11. Global Summary of Spinal Cord Injury, Incidence, and Economic Impact.
International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP),
October 2001.
12. Center for Devices and Radiological Health, U.S. Food and Drug Administration
(httIA:\./v._.I da
uv/cdrlv)
13. North American Science Associates (NAMSA)
.11tt,:
jI\\
iI.ii...
l..
29
14. GMP Companies, Inc. (http://!www.lmpcompanitl s.co)
15. GMP Companies, Inc.
(lttp:i.'vN-\ .igmpcoliLpanies.co(hil site/rseirclhandde/subpages,/te.cvai
.till
1)
30
Appendix A: MIT Patents Licensed to GMP Companies, Inc.
1.
M.I.T. Case No. 3946, "Novel Non-Peptide Bioerodible Polymers Based On
Naturally Occurring X-Amino Acids," by Joachim B. Kohn and Robert S. Langer
United States of America Patent No. 4638045, Issued January 20, 1987
"Non-Peptide Polyamino Acid Bioerodible Polymers", by Joachim B.
Kohn and Robert S. Langer
2.
M.I.T. Case No. 4051, "The Use Of Biodegradable Poly (Iminocarbonates) As
Biomaterials For Medical Applications," by Joachim B. Kohn and Robert S.
Langer
United States of America Patent No. 4806621, Issued February 21, 1989
"Biocompatible Bioerodible Hydrophobic Implantable Polyamino
Carbonate Article", by Joachim B. Kohn and Robert S. Langer
3.
M.I.T. Case No. 4279, "Controlled Cellular Implantation Using Artificial
Matrices," by Robert S. Langer and Joseph P. Vacanti
Japan Patent No. 2067741, Issued July 10, 1996
"Chemical Neomorphogenesis Of Organs By Controlled Cellular
Implantation Using Artificial Matrices."
Canada Patent No. 1340581, Issued June 8, 1999
United States of America Patent No. 5759830, Issued June 2, 1998
United States of America Patent No. 5770193, Issued June 23, 1998
United States of America Patent No. 5770417, Issued June 23, 1998
"Chimeric Neomorphogenesis Of Organs By Controlled Cellular
Implantation Using Artificial Matrices"
Austria Patent No. E139432, Issued June 19, 1996
Belgium Patent No. 0299010, Issued June 19, 1996
European Patent Convention Patent No. 0299010, Issued June 19, 1996
France Patent No. 0299010, Issued June 19, 1996
Germany Patent No. P3751843.7, Issued June 19, 1996
Italy Patent No. 0299010, Issued June 19, 1996
Luxembourg Patent No. 0299010, Issued June 19, 1996
Netherlands Patent No. 0299010, Issued June 19, 1996
Sweden Patent No. 0299010, Issued June 19, 1996
Switzerland Patent No. 0299010, Issued June 19, 1996
United Kingdom Patent No. 0299010, Issued June 19, 1996
"Chimeric Neomorphogenisis Of Organs By Controlled Cellular
Implantation Using Artificial Matrices"
by Robert S. Langer and Joseph P. Vacanti
31
4.
M.I.T. Case No. 4332, "Biodegradable Materials For The Regeneration Of
Tissues," by Ariel G. Ferdman, Elaine Lee and Ioannis V. Yannas
United States of America Patent No. 4947840, Issued August 14, 1990
"Biodegradable Templates For The Regeneration Of Tissues"
by Ariel G. Ferdman, Elaine Lee and Ioannis V. Yann
5.
M.I.T. Case No. 4371, "Hydroxamic Acid Polymers From Primary Amide
Polymers," by Ernest G. Cravalho, Abraham J. Domb, Gershon Golumb, Robert
S. Langer, Cato T. Laurencin and Edith Mathiowitz
United States of America Patent No. 5,128,420, Issued July 7, 1992
"Method of Making Hydroxamic Acid Polymers From Primary Amide
Polymers, by Ernest G. Cravalho, Abraham J. Domb, Gershon Golumb,
Robert S. Langer, Cato T. Laurencin and Edith Mathiowitz
6.
M.I.T. Case No. 4973, "Method Of Implanting Large Cell Volume On A
Polymeric Matrix," by Lynt Johnson, Robert S. Langer and Joseph P. Vacanti
Australia Patent No. 636346, Issued August 23, 1993
Austria Patent No. El119787, Issued October 25, 1995
Belgium Patent No. 0422209, Issued October 5, 1995
Canada Patent No. 2031532, Issued February 25, 2003
France Patent No. 0422209, Issued October 5, 1995
Germany Patent No. 69017820, Issued October 5, 1995
Italy Patent No. 0422209, Issued October 5, 1995
Japan Patent No. 3073766, Issued June 2, 2000
Netherlands Patent No. 0422209, Issued October 5, 1995
Spain Patent No. 0422209, Issued October 5, 1995
Sweden Patent No. 0422209, Issued March 15, 1995
Switzerland Patent No. 0422209, Issued October 5, 1995
United Kingdom Patent No. 0422209, Issued October 5, 1995
United States of America Patent No. 5804178, Issued September 8, 1998
"Method For Implanting Large Volumes Of Cells On Polymeric Matrices"
by Lynt Johnson, Robert S. Langer and Joseph P. Vacanti
7.
M.I.T. Case No. 5573, "Preparation Of Highly-Porous Biodegradable Polymer
Membranes By A Particulate-Leaching Technique," by Linda G. Griffith, Robert
S. Langer, Antonios G. Mikos, Georgios Sarakinos and Joseph P. Vacanti
United States of America Patent No. 5514378, Issued May 7, 1996
"Biocompatible Polymer Membranes And Methods Of Preparation Of
Three Dimensional Membrane Structures"
by Linda G. Griffith, Robert S. Langer, Antonios G. Mikos, Georgios
Sarakinos and Joseph P. Vacanti
32
8.
M.I.T. Case No. 5729, "Prevascularized Polymeric Implants For Organ
Transplantation," by James C. Gilbert, Donald E. Ingber, Robert S. Langer, James
E. Stein and Joseph P. Vacanti
Austria Patent No. 0610423, Issued May 7, 1997
Belgium Patent No. 0610423, Issued May 7, 1997
Canada Serial No. 2121040, Filed October 28, 1992
European Patent Convention Patent No. 0610423, Issued May 7, 1997
France Patent No. 0610423, Issued May 7, 1997
Germany Patent No. 69219613, Issued May 7, 1997
Italy Patent No. 0610423, Issued May 7, 1997
Japan Patent No. 3524919, Issued February 20, 2004
Japan Serial No. 2001-397626, Filed October 28, 1992
Luxembourg Patent No. 0610423, Issued May 7, 1997
Netherlands Patent No. 0610423, Issued May 7, 1997
Sweden Patent No. 0610423, Issued May 7, 1997
United Kingdom Patent No. 0610423, Issued May 7, 1997
United States of America Patent No. 6309635, Issued October 30, 2001
United States of America Serial No. 09/942535, Filed August 29, 2001
"Prevascularized Polymeric Implants For Organ Transplantation"
by James C. Gilbert, Donald E. Ingber, Robert S. Langer, James E. Stein
and Joseph P. Vacanti
9.
M.I.T. Case No. 6560, "Porous Biodegradable Polymeric Materials For Cell
Transplantation," by Linda G. Griffith, Donald E. Ingber, Robert S. Langer,
Antonios G. Mikos, Georgios Sarakinos and Joseph P. Vacanti
United States of America Patent No. 6689608, Issued February 10, 2004
United States of America Serial No. 10/775768, Filed February 10, 2004
"Porous Biodegradable Polymeric Materials For Cell Transplantation"
by Linda G. Griffith, Donald E. Ingber, Robert S. Langer, Antonios G.
Mikos, Georgios Sarakinos and Joseph P. Vacanti
10.
M.I.T. Case No. 6798, "Localized Delivery Of Growth Factors To Transplanted
Cells," by Robert S. Langer, David J. Mooney and Joseph P. Vacanti
Austria Patent No. 0794790, Issued April 17, 2002
Belgium Patent No. 0794790, Issued April 17, 2002
Canada Patent No. 2207286, Issued October 7, 2003
Denmark Patent No. 0794790, Issued April 17, 2002
European Patent Convention Patent No. 0794790, Issued April 17, 2002
France Patent No. 0794790, Issued April 17, 2002
Germany Patent No. 0794790, Issued April 17, 2002
Greece Patent No. 0794790, Issued April 17, 2002
Ireland Patent No. 0794790, Issued April 17, 2002
33
Italy Patent No. 0794790, Issued April 17, 2002
Japan Serial No. 8-519275, Filed December 14, 1995
Liechtenstein Patent No. 0794790, Issued April 17, 2002
Luxembourg Patent No. 0794790, Issued April 17, 2002
Monaco Patent No. 0794790, Issued April 17, 2002
Netherlands Patent No. 0794790, Issued April 17, 2002
Portugal Patent No. 0794790, Issued April 17, 2002
Spain Patent No. 0794790, Issued April 17, 2002
Sweden Patent No. 0794790, Issued April 17, 2002
Switzerland Patent No. 0794790, Issued April 17, 2002
United Kingdom Patent No. 0794790, Issued April 17, 2002
United States of America Patent No. 6281015, Issued August 28, 2001
"Localized Delivery Of Factors Enhancing Survival Of Transplanted
Cells", by Robert S. Langer, David J. Mooney and Joseph P. Vacanti
11.
M.I.T. Case No. 6984, "Functional, Degradable Poly(Lactic Acid-Co-Amino
Acid) Graft Copolymers," by Jeffrey S. Hrkach, Robert S. Langer and Noah
Lotan
United States of America Patent No. 5654381, Issued August 5, 1997
"Functionalized Polyester Graft Copolymers"
by Jeffrey S. Hrkach, Robert S. Langer and Noah Lotan
12.
M.I.T. Case No. 7138, "Neuronal Stimulation Using An Electrically Conductive
Polymer-Polypyrrole," by Robert S. Langer, Christine E. Schmidt, Venkatram P.
Shastri and Joseph P. Vacanti
Australia Patent No. 720275, Issued September 11, 2000
Canada Serial No. 2236749, Filed October 31, 1996
European Patent Convention Serial No. 96937894.2, Filed October 31,
1996
Japan Serial No. 9-517608, Filed October 31, 1996
Korea (south) Serial No. 98-703320, Filed October 31, 1996
New Zealand Patent No. 321886, Issued June 8, 2000
United States of America Patent No. 6095148, Issued August 1, 2000
"Neuronal Stimulation Using Electrically Conducting Polymers"
by Robert S. Langer, Christine E. Schmidt, Venkatram P. Shastri and
Joseph P. Vacanti
34